Jpn. J. Med. Mycol. Vol. 46, 217222, 2005 ISSN 09164804,,,. echinocandin, pneumocandin. FR901379,., 1,3--D-glucan,,,., in vitro.,.,,. 2002,., 3,. Key words: micafungin, echinocandin, 1,3--D- 1,3--D-glucan synthase, candidiasis, aspergillosis 1.,,,.,.,, 5,,,.,.,,,., 1,3--D-glucan,, 1, 2. 541-8514 3-4-7 Coleophoma empetri FR901379, Fig. 1, 35., 2002, 3.,,,. 2. 1 1,3--D-glucan,. C. albicans A. fumigatus 1,3--D-glucan UDP-[ 14 ]-glucose, glucan, Ki Dixon plot C. albicans A. fumigatus 1,3--D-glucan Ki 0.208M
218 46 4 17 3 C S 3 Na N 2 N N N 3 C N N C 3 N N N Fig. 1. Chemical structure of micafungin sodium. 1/v (1/nmoles of UDP-glucose incorporated/min/mg of protein) (A) (B) Fig. 2. Kinetics of micafungin MCFGinhibition against 1,3--D-glucan synthase in crude lysate of C. albicans ATCC 90028 A and A. fumigatus TIMM 0063 B. Glucan syntheses were run with different concentrations of UDP-glucose ranging from 0.25 mm to 1 mm, with MCFG. 6 0.0158M,, 6 Fig. 2. C. albicans, A. fumigatus 7. 1,3--D-glucan,. 2in vitro,., C. albicans C. glabrata C. krusei
Jpn. J. Med. Mycol. Vol. 46 No. 4, 2005 219 Table 1. MICs of MCFG against clinical isolates of Candida and Aspergillus species rgaism MIC range MIC 50 MIC 90 Compound no. of isolates g/ml g/ml g/ml MCFG 0.0078-0.0625 0.0156 0.0313 C. albicans FLCZ 0.0625-4 0.25 0.5 55 ITCZ 0.0078-0.125 0.0313 0.0625 AMP-B 0.0625-1 0.5 0.5 MCFG 0.0156-0.0313 0.0156 0.0313 C. albicans FLCZ-resistant FLCZ 16-64 64 64 4 ITCZ 1-8 8 8 AMP-B 0.25-0.5 0.5 0.5 MCFG 0.0156-0.0625 0.0313 0.0625 C. tropicalis FLCZ 0.0625-64 0.25 2 42 ITCZ 0.0078-2 0.0625 0.5 AMP-B 0.125-1 0.5 0.5 MCFG 0.0156-0.0625 0.0156 0.0313 C. glabrata FLCZ 1-64 4 32 36 ITCZ 0.125-8 0.5 1 AMP-B 0.125-1 0.5 1 MCFG 0.125 0.0125 0.125 C. krusei FLCZ 1-64 32 32 11 ITCZ 0.125-1 0.5 1 AMP-B 1 1 1 MCFG 0.5-4 1 4 C. parapsilosis FLCZ 0.125-4 0.5 1 28 ITCZ 0.0313-0.5 0.125 0.5 AMP-B 0.125-1 0.5 1 MCFG 0.25-8 1 2 C. guilliermondii FLCZ 1-16 4 8 29 ITCZ 0.125-1 0.5 1 AMP-B 0.125-1 0.5 0.5 MCFG 0.0078-0.0313 0.0156 0.0313 A. fumigatus FLCZ 8-64 64 64 39 ITCZ 0.0625-1 0.5 1 AMP-B 0.25-2 1 2 MCFG 0.0078-0.0625 0.0156 0.0313 A. niger FLCZ 64-64 64 64 11 ITCZ 0.5-1 1 1 AMP-B 0.5-2 1 1 MCFG 0.0078-0.0625 0.0156 0.0313 A. flavus FLCZ 2-64 64 64 11 ITCZ 0.0625-0.5 0.25 0.5 AMP-B 0.25-2 2 2 MCFG 0.0039-0.0156 0.0078 0.0156 A. terreus FLCZ 4-64 16 64 6 ITCZ 0.0625-0.25 0.125 0.25 AMP-B 0.25-2 0.5 2 Medium: RPMI1640/165 mm MPS p 7.0 MIC 50 or MIC 90: The MICs at which 50 or 90% of isolates are inhibited, respectively MCFG: micafungin, FLCZ: fluconazole, ITCZ: itraconazole, AMP-B: amphotericin B 5 5 Table 1., A. fumigatus. 3in vivo C. albicans, C. glabrata, C. tropicalis, C. krusei, 50 ED 50 0.141.61 mg/kg, B, 8 Table 2., A.
220 46 4 17 Table 2. Efficacy of micafungin in neutropenic mouse models of disseminated candidiasis and pulmonary aspergillosis Inoculum ED 50: mg/kg 95% confidence intervals rganism CFU MCFG FLCZ ITCZ AMP-B C. albicans FP1840 8.410 3 0.38 17.2 37.2 0.16 0.27-0.54 12.2-40.2 25.9-55.7 0.12-0.23 C. glabrata 16011 4.010 7 0.18 4.89 16.9 0.10 0.12-0.26 3.37-6.97 10.2-24.0 0.07-0.13 C. tropicalis 16004 3.610 4 0.35 7.2 62.0 0.21 0.26-0.48 44.2-98.0 0.15-0.29 C. krusei 15001 7.210 7 1.61 20.0 80.0 0.71 1.11-3.98 0.46-2.04 A. fumigatus TIMM 0063 8.010 5 0.33 20.0 28.3 0.25 0.23-0.45 20.5-38.6 0.16-0.36 A. fumigatus IFM 40835 8.310 5 0.26 20.0 34.0 0.25 0.18-0.36 0.16-0.36 A. fumigatus IFM 40836 7.010 5 0.45 20.0 40.3 0.46 0.32-0.64 28.0-62.4 0.31-0.76 Mice: ICR strain, male, 4-weeks-old, 8 mice per group Cyclophosphamide was intraperitoneally administered at 200 mg/kg 4 days before and 1 day afier infection Infection: Each strain of Candida species was inoculated intravenously and each strain of A. fumigatus was inoculated intranasally Treatment: nce daily for 4 days starting 1 hour after infection by intravenous administration. ITCZ was orally administered using the same regimen ED 50: Calculated based on the survival rate 15 days after infection by probit analysis or normal probability plot. Not calculated MCFG: micafungin, FLCZ: fluconazole, ITCZ: itraconazole, AMP-B: amphotericin B 8, 9 fumigatus ED 50 0.260.45 mg/kg, B, 9 Table 2. 4 B,,, 10. B,, 2., in vitro 10,. 3. 25, 50, 75 mg 30, 150 mg 1 t 1/2, Vd ss, CL t, t 1/2 13.91.0, Vd ss 0.2280.016 l/kg, CL t 0.1970.018 ml /min/kg, AUC 0-11., 75 mg/day 1 1 7,, 4 11.,, 25150 mg., 6678 2024, C max, AUC 0 -, t 1/2, Vd ss, CL t 12., Child-Pugh 7.6 20 ml/min/m 2 13., 14 C, 7 7.4 43.8, 13. CYP, CYP1A2, 2C9, 2C19, 2D6 2E1 7-,, S-, 14.
Jpn. J. Med. Mycol. Vol. 46 No. 4, 2005 221 CYP3A 50 mol/l 65g/ml, 150 mg C max 15g/ml 0.3, 40 ng/ml, CYP3A 14.,,,,, 13. 4., 70,.,, 25 mg/ 28.6 2/7, 50 mg/, 75 mg/, 150 mg/ 71.4 5/7, 57.1 8/14, 69.2 9/ 13 15.,, 50150 mg/ 60.0 6/10, 150 mg/ 80.0 4/5.,, 2575 mg/ 6/6,, 50 mg/ 75 mg/ 5/5. 17.9 12/67, 2,,,,,,,,,, 1.,, Al-P, BUN 16.4 11/67 15., 1,,,. 5.,.,. B,.,.., 1,3--D-glucan,,., CYP 2001,.,,.,.,,.,,. 1. 41: 221228, 2000. 2. 49: 535 545, 2001. 3Iwamoto T, Fujie A, Nitta K, ashimoto S, kuhara M, Kohsaka M: WF11899A, B and C, novel antifungal lipopeptides. I. Taxonomy, fermentation, isolation and physico-chemical properties. J Antibiot 47 1084 1091, 1994. 4Tomishima M, hki, Yamada A, Takasugi, Maki K, Tawara S, Tanaka : FK463, a novel water-soluble echinocandin lipopeptide: Synthesis and antifungal activity. J Antibiot 52 674676, 1999. 5,,,,,,,, : micafungin in vitro. 50S-1: 819, 2002. 6atano K, Morishita Y, Nakai T, Ikeda F: Antifungal mechanism of FK463 against Candida albicans and Aspergillus fumigatus. J Antibiot 55: 219222, 2002 7 :. 33: 2328, 2003. 8,,,,,,,, : Candida Aspergillus fumigatus micafungin. 50S -1: 3036, 2002. 9,,,,,,,, : Aspergillus fumigatus micafungin. 50S -1: 3742, 2002. 10,,,,,,,,,, Micafungin amphotericin B, itraconazole fluconazole. 50S -1 5867.
222 46 4 17 11,,,,, : Micafungin. 50 S -1: 155184, 2002 12,,,,, : Micafungin. 50S -1: 148154, 2002 13 : Pharmacokinetics. 33: 2934, 2003. 14,,,,,,, : In vitro micafungin. 50S -1: 94103, 2002. 15Kohno S, Masaoka T, Yamaguchi, Mori T, Urabe A, Ito A, Niki Y, Ikemoto : A multicenter, openlabel clinical study of micafungin in the treatment of deep-seated mycosis. Scand J Infect Dis 365: 372 379, 2004. Antifungal Activity and Clinical Efficacy of Micafungin Funguard. Fumiaki Ikeda Post Marketing Product Development, Astellas Pharma Inc. 3-4-7 Doshomachi, Chuo-ku, saka 541-8514, Japan Micafungin MCFGis a new lipopeptide antifungal agent of the echinocandin class. MCFG inhibits 1,3- -D-glucan synthesis in C. albicans and A. fumigatus in a non-competitive manner, and has antifungal activity against both Aspergillus and Candida species. In neutropenic mouse models of disseminated candidiasis and pulmonary aspergillosis, the efficacy of MCFG was superior to that of fluconazole and itraconazole, but comparable to that of amphotericin B. The efficacy and safety of MCFG were investigated in 70 patients with deep-seated mycosis caused by Candida and Aspergillus species. The overall clinical response rates were 57.1% in aspergillosis and 78.6% in candidiasis. The incidence of adverse events related to micafungin was 17.9%, and there was no dose-related occurrence of any adverse events. The results from this study indicated that micafungin was effective in aspergillosis and candidiasis, with no tolerability problems., 48 1 :.